Protein Interacting with C-Kinase 1/Protein Kinase Cα-Mediated Endocytosis Converts Netrin-1-Mediated Repulsion to Attraction
| Autor: | Joseph L. Bartoe, Jun Xia, Lindsay Hinck, Kogo Takamiya, William L. McKenna, Tiffani K. Quan, Jenna A. Moore, Richard L. Huganir, Benjamin K. Stafford |
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| Rok vydání: | 2006 |
| Předmět: |
Central Nervous System
Protein Kinase C-alpha Deleted in Colorectal Cancer media_common.quotation_subject Growth Cones Receptors Cell Surface Cell Communication Biology Endocytosis Hippocampus Cerebellar Cortex Mice Chemorepulsion Netrin Animals Nerve Growth Factors Phosphorylation Protein kinase A Internalization Cells Cultured media_common Mice Knockout Chemotactic Factors Chemotaxis Tumor Suppressor Proteins General Neuroscience Cell Membrane fungi Nuclear Proteins Articles Netrin-1 Rats Cell biology Enzyme Activation Cytoskeletal Proteins nervous system Axon guidance Cues Carrier Proteins Netrin Receptors PICK1 |
| Zdroj: | The Journal of Neuroscience. 26:3192-3205 |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.3469-05.2006 |
| Popis: | In vertebrates, the receptor families deleted in colorectal cancer (DCC) and UNC5 mediate responses to the bifunctional guidance cue netrin-1. DCC mediates attraction, whereas a complex of DCC and UNC5 mediates repulsion. Thus, a primary determinant of the responsiveness of an axon to netrin-1 is the presence or absence of UNC5 family members on the cell surface. Currently, little is known about the role of receptor trafficking in regulating neuronal responses to netrin-1. We show that protein interacting with C-kinase 1 (PICK1) recruits activated protein kinase Cα (PKCα) to MycUNC5A at the plasma membrane, stimulating its endocytosis. We identify two PKCα phosphorylation sites at serines 408 and 587, as well as dileucine internalization motifs, which are required for this endocytosis. We find that PKCα-stimulated internalization of UNC5A alters the functional response of developing hippocampal axons to netrin-1, preventing UNC5A-mediated growth cone collapse and converting netrin-1-stimulated chemorepulsion to attraction. To address whether this conversion in axonal response occurs in neurons expressing endogenous levels of UNC5, we show that mouse cerebellar granule axons exhibit chemorepulsion in a netrin-1 gradient and that this chemorepulsion is converted to chemoattraction after PKCα activation. We demonstrate that this repulsion depends on UNC5A becauseUnc5a−/− axons are not repelled and show this conversion depends on PICK1 becausePICK1−/− axons are not converted to chemoattraction after PKCα activation. Together, these data provide a potential mechanism to explain how developing neurons alter their responsiveness to netrin-1 at intermediate choice points as they navigate to their targets. |
| Databáze: | OpenAIRE |
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